In accordance with the present invention, there is provided a method for retaining ophthalmological agents in ocular tissues comprising complexing an ophthalmological drug or reagent with a sulfated glucan sulfate such as cyclodextrin sulfate and contacting the complex so formed with the ocular tissue.
One of the most frequently discussed problems in ocular therapeutics is the delivery of optimal concentrations of ophthalmological agents at the site of action. This problem is due to a number of factors including the distance between where the drug is administered and where it acts, and the physiological processes which reduce drug concentration as it moves from its administration site to its action site. These processes can be grouped into three categories based on anatomical considerations. See Mishima et al, Survey of Ophthalmology Vol.29, No.5 at 335-348 (1985). The first is tear dynamics, conjunctival and scleral absorption. Second is interaction with the cornea. Third is intraocular distribution including aqueous humor turnover. The extent to which such processes are involved in ocular drug bioavailability is often modified by the physical and chemical properties of the drug as well as by the physical properties of the vehicle used in conjunction with the ocular drug or reagent.
Precorneal drug loss, e.g., precorneal fluid dynamics, plays an exceedingly important role in controlling the amount of drug available for corneal absorption. It is principally influenced by the nature of the vehicle applied. Liquid vehicles, which include liposomes, are subjected to drainage into the nasolacrimal apparatus immediately following instillation, a process whose efficiency is highly dependent on the volume, pH, tonicity, and viscosity of the liquid instilled. In addition, the drug would be diluted by tears secreted by the lacrimal glands and may be lost to the tear proteins as a result of binding, thus further reducing the amount of drug available for corneal absorption.
Drug absorption into the conjunctiva is another route of precorneal drug loss. A portion of the drug lost to the conjunctiva may, however, eventually gain entry to the internal eye. While drug loss to precorneal fluid dynamics is primarily a function of the nature of the drug vehicle, corneal drug absorption is principally controlled by the physical and chemical properties of a drug relative to the properties of the cornea. Of the drug properties, lipophilicity and molecular size play a more important role in corneal drug transport.
In recent years, the traditional view of the cornea as a physical barrier to drug transport has been expanded to include its capacity to metabolize certain drugs in transit. Progress in this area is enhanced by ongoing research efforts in unraveling the full complement of enzyme systems participating in corneal drug metabolism. Among the metabolic enzymes that have been identified are the esterases, catechol-0-methyl transferase, monoamine oxidase, arylhydrocarbon hydroxylase, UDP-glucuronyl transferase, acid phosphatase, beta-glucuronidase, and arylsulfatase. Both direct and indirect evidence indicates localization of these enzymes in the corneal epithelium. Interaction of the vast majority of drugs with these corneal enzymes usually results in a reduction of the amount of drug available for interaction with drug receptors within the eye. This event is, therefore, undesirable.
The vehicle in which a drug is housed can influence the rate and extent of topical ocular drug absorption in several ways: (1) by affecting the duration over which the drug remains in the tear chamber; (2) by affecting the rate of drug release; and (3) by the manner in which the vehicle itself interacts with the corneal epithelial surface. These factors, in turn, are affected by the additives such as buffers, polymers, and preservatives in a given vehicle, by the drug concentration in the vehicle, and by the frequency and order of administration of the vehicle.
The vehicles that are currently commercially available include aqueous solutions, suspensions, ointments, and the Ocusert.sup.R. Those that are potentially useful include gels, erodible and nonerodible inserts, emulsions, microcapsules, and liposomes. To this list may be added a bioadhesive polymeric system, which is under investigation for oral controlled drug delivery but which can be adapted to control the delivery for ophthalmic drugs.
In the category of potentially useful vehicles, the gels and inserts are the more widely studied. Grass et al., found that erodible films made of 20% polyvinyl alcohol and containing pilocarpine amplified the maximum change in miosis and the duration of miosis in the albino rabbit by a factor of 2 and 5 respectively. Using a similar polymeric film, Saettone et al. demonstrated a twofold increase in the ocular bioavailability of pilocarpine over a aqueous solution in albino rabbits. Moreover, these investigators found that complexing pilocarpine with poly(acrylic acid) further enhanced the ocular bioavailability of pilocarpine by another factor of two. Using polyacrylamide and a copolymer of acrylamide, N-vinylpyrrolidone, and ethyl acrylate as a drug delivery matrix, Urtti et al. observed a threefold increase in the ocular bioavailability of pilocarpine in both albino and pigmented rabbits. In all three instances, the enhanced drug effectiveness was attributed to improved contact time of the vehicle with the cornea.
Unlike ointments and inserts, vehicles such as suspensions, emulsions, microcapsules, and liposomes are liquid-like. As such, they are subjected to removal from the conjunctival sac via drainage, resulting in a residence time of 30 minutes or less in the tear pool. This drainage rate is slightly dependent on the physical nature of the vehicle. For instance, suspensions have been found to be retained in the conjunctival sac longer than solutions. It is expected that other dispersed systems such as liposomes, emulsions, and microcapsules would behave similarly. Although these vehicles remain in the conjunctival sac longer than aqueous solutions, they would be therapeutically useful only if they consistently release the drug at an optimal rate, through a combination of such processes a dissolution, diffusion and partitioning. This is because, unlike solutions, the drug in these vehicles is not immediately available for corneal absorption.
To date, the manner in which liquid vehicles interact with the corneal surface has been neither well studied nor exploited for controlling corneal drug absorption. Obviously, vehicles that may have an affinity for the corneal surface, as exemplified by bioadhesive polymers, must overcome the natural tendency of the cornea to rid its surface of foreign substances. Although a judicious selection of emulsifying agents, polymers, and phospholipids, dispersed systems like emulsions, microcapsules, and liposomes may achieve this goal, it is apparent that continuing efforts will be required to prolong ophthalmological drug action by lengthening the time that the drug or reagent is in the eye.